tbuckley/cabot-search huggingface dataset:
A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models
Authors: Bettina van Lengerich, Lihong Zhan, Dan Xia, Darren Chan, David Joy, Joshua I. Park, David Tatarakis, Meredith Calvert, Selina Hummel, Steve Lianoglou, Michelle E. Pizzo, Rachel Prorok, Elliot Thomsen, Laura M. Bartos, Philipp Beumers, Anja Capell, Sonnet S. Davis, Lis de Weerd, Jason C. Dugas, Joseph Duque, Timothy Earr, Kapil Gadkar, Tina Giese, Audrey Gill, Johannes Gnörich, Connie Ha, Malavika Kannuswamy, Do Jin Kim, Sebastian T. Kunte, Lea H. Kunze, Diana Lac, Kendra Lechtenberg, Amy Wing-Sze Leung, Chun-Chi Liang, Isabel Lopez, Paul McQuade, Anuja Modi, Vanessa O. Torres, Hoang N. Nguyen, Ida Pesämaa, Nicholas Propson, Marvin Reich, Yaneth Robles-Colmenares, Kai Schlepckow, Luna Slemann, Hilda Solanoy, Jung H. Suh, Robert G. Thorne, Chandler Vieira, Karin Wind-Mark, Ken Xiong, Y. Joy Yu Zuchero, Dolo Diaz, Mark S. Dennis, Fen Huang, Kimberly Scearce-Levie, Ryan J. Watts, Christian Haass, Joseph W. Lewcock, Gilbert Di Paolo, Matthias Brendel, Pascal E. Sanchez, Kathryn M. Monroe
Journal: Nature Neuroscience (2023)

Abstract Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
Impaired CD4+ T cell response in older adults is associated with reduced immunogenicity and reactogenicity of mRNA COVID-19 vaccination
Authors: Norihide Jo, Yu Hidaka, Osamu Kikuchi, Masaru Fukahori, Takeshi Sawada, Masahiko Aoki, Masaki Yamamoto, Miki Nagao, Satoshi Morita, Takako E. Nakajima, Manabu Muto, Yoko Hamazaki
Journal: Nature Aging (2023)

Abstract Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort ( n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4 + T cells including CXCR3 + circulating follicular helper T cells and the T H 1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific T H 1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8 + T cell responses. Thus, an inefficient CD4 + T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4 + T cell response following the first dose is key to improving vaccine efficacy in older adults.
Exposure to negative socio-emotional events induces sustained alteration of resting-state brain networks in older adults
Authors: Sebastian Baez-Lugo, Yacila I. Deza-Araujo, Christel Maradan, Fabienne Collette, Antoine Lutz, Natalie L. Marchant, Gaël Chételat, Patrik Vuilleumier, Olga Klimecki, Eider Arenaza-Urquijo, Claire André, Maelle Botton, Pauline Cantou, Gaëlle Chételat, Anne Chocat, Vincent De la Sayette, Marion Delarue, Stéphanie Egret, Eglantine Ferrand Devouge, Eric Frison, Julie Gonneaud, Marc Heidmann, Elizabeth Kuhn, Brigitte Landeau, Gwendoline Le Du, Valérie Lefranc, Florence Mezenge, Inès Moulinet, Valentin Ourry, Géraldine Poisnel, Anne Quillard, Géraldine Rauchs, Stéphane Rehel, Clémence Tomadesso, Edelweiss Touron, Caitlin Ware, Miranka Wirth
Journal: Nature Aging (2023)
Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy
Authors: Yi You, Yu Tian, Zhaogang Yang, Junfeng Shi, Kwang Joo Kwak, Yuhao Tong, Andreanne Poppy Estania, Jianhong Cao, Wei-Hsiang Hsu, Yutong Liu, Chi-Ling Chiang, Benjamin R. Schrank, Kristin Huntoon, DaeYong Lee, Ziwei Li, Yarong Zhao, Huan Zhang, Thomas D. Gallup, JongHoon Ha, Shiyan Dong, Xuefeng Li, Yifan Wang, Wen-Jing Lu, Eman Bahrani, Ly James Lee, Lesheng Teng, Wen Jiang, Feng Lan, Betty Y. S. Kim, Andrew S. Lee
Journal: Nature Biomedical Engineering (2023)
Regional and country-level trends in cervical cancer screening coverage in sub-Saharan Africa: A systematic analysis of population-based surveys (2000–2020)
Authors: Lily Yang, Marie-Claude Boily, Minttu M. Rönn, Dorcas Obiri-Yeboah, Imran Morhason-Bello, Nicolas Meda, Olga Lompo, Philippe Mayaud, Michael Pickles, Marc Brisson, Caroline Hodgins, Sinead Delany-Moretlwe, Mathieu Maheu-Giroux
Journal: PLoS Medicine (2023)

Sub-Saharan Africa (SSA) has the highest cervical cancer (CC) burden globally-worsened by its HIV epidemics. In 2020, the World Health Organization (WHO) introduced a CC elimination strategy with goals for vaccination, screening, and treatment. To benchmark progress, we examined temporal trends in screening coverage, percent screened at least twice by the age of 45, screening coverage among women living with HIV (WLHIV), and pre-cancer treatment coverage in SSA.
Sybil: A Validated Deep Learning Model to Predict Future Lung Cancer Risk From a Single Low-Dose Chest Computed Tomography
Authors: Peter G. Mikhael, Jeremy Wohlwend, Adam Yala, Ludvig Karstens, Justin Xiang, Angelo K. Takigami, Patrick P. Bourgouin, PuiYee Chan, Sofiane Mrah, Wael Amayri, Yu-Hsiang Juan, Cheng-Ta Yang, Yung-Liang Wan, Gigin Lin, Lecia V. Sequist, Florian J. Fintelmann, Regina Barzilay
Journal: Journal of Clinical Oncology (2023)

PURPOSE Low-dose computed tomography (LDCT) for lung cancer screening is effective, although most eligible people are not being screened. Tools that provide personalized future cancer risk assessment could focus approaches toward those most likely to benefit. We hypothesized that a deep learning model assessing the entire volumetric LDCT data could be built to predict individual risk without requiring additional demographic or clinical data. METHODS We developed a model called Sybil using LDCTs from the National Lung Screening Trial (NLST). Sybil requires only one LDCT and does not require clinical data or radiologist annotations; it can run in real time in the background on a radiology reading station. Sybil was validated on three independent data sets: a heldout set of 6,282 LDCTs from NLST participants, 8,821 LDCTs from Massachusetts General Hospital (MGH), and 12,280 LDCTs from Chang Gung Memorial Hospital (CGMH, which included people with a range of smoking history including nonsmokers). RESULTS Sybil achieved area under the receiver-operator curves for lung cancer prediction at 1 year of 0.92 (95% CI, 0.88 to 0.95) on NLST, 0.86 (95% CI, 0.82 to 0.90) on MGH, and 0.94 (95% CI, 0.91 to 1.00) on CGMH external validation sets. Concordance indices over 6 years were 0.75 (95% CI, 0.72 to 0.78), 0.81 (95% CI, 0.77 to 0.85), and 0.80 (95% CI, 0.75 to 0.86) for NLST, MGH, and CGMH, respectively. CONCLUSION Sybil can accurately predict an individual's future lung cancer risk from a single LDCT scan to further enable personalized screening. Future study is required to understand Sybil's clinical applications. Our model and annotations are publicly available. [Media: see text]
Inferring the multiplicity of founder variants initiating HIV-1 infection: a systematic review and individual patient data meta-analysis
Authors: James Baxter, Sarah Langhorne, Ting Shi, Damien C Tully, Ch Julián Villabona-Arenas, Stéphane Hué, Jan Albert, Andrew Leigh Brown, Katherine E Atkins
Journal: The Lancet Microbe (2023)
Diabetes and cirrhosis: Current concepts on diagnosis and management
Authors: Laurent Castera, Kenneth Cusi
Journal: Hepatology (2023)

Type 2 diabetes mellitus is often associated with cirrhosis as comorbidities, acute illness, medications, and other conditions profoundly alter glucose metabolism. Both conditions are closely related in NAFLD, the leading cause of chronic liver disease, and given its rising burden worldwide, management of type 2 diabetes mellitus in cirrhosis will be an increasingly common dilemma. Having diabetes increases cirrhosis-related complications, including HCC as well as overall mortality. In the absence of effective treatments for cirrhosis, patients with type 2 diabetes mellitus should be systematically screened as early as possible for NAFLD-related fibrosis/cirrhosis using noninvasive tools, starting with a FIB-4 index followed by transient elastography, if available. In people with cirrhosis, an early diagnosis of diabetes is critical for an optimal management strategy (ie, nutritional goals, and glycemic targets). Diagnosis of diabetes may be missed if based on A1C in patients with cirrhosis and impaired liver function (Child-Pugh B–C) as anemia may turn the test unreliable. Clinicians must also become aware of their high risk of hypoglycemia, especially in decompensated cirrhosis where insulin is the only therapy. Care should be within multidisciplinary teams (nutritionists, obesity management teams, endocrinologists, hepatologists, and others) and take advantage of novel glucose-monitoring devices. Clinicians should become familiar with the safety and efficacy of diabetes medications for patients with advanced fibrosis and compensated cirrhosis. Management is conditioned by whether the patient has either compensated or decompensated cirrhosis. This review gives an update on the complex relationship between cirrhosis and type 2 diabetes mellitus, with a focus on its diagnosis and treatment, and highlights knowledge gaps and future directions.
Targeting VPS72 inhibits ACTL6A/MYC axis activity in HCC progression
Authors: Furong Liu, Zhibin Liao, Lu Qin, Ze Zhang, Qiaofeng Zhang, Shenqi Han, Weifeng Zeng, Hongwei Zhang, Yachong Liu, Jia Song, Wei Chen, He Zhu, Huifang Liang, Xiaoping Chen, Bixiang Zhang, Zhanguo Zhang
Journal: Hepatology (2023)

Background and Aims: HCC is a highly heterogeneous disease that is caused largely by genomic copy number variations. Herein, the mechanistic and therapeutically targeted role of vacuolar protein sorting 72 homologue (VPS72), a novel copy number variation cis-driven gained gene identified by genome-wide copy number variation and transcriptome analyses in HCC, is not well understood. Approach and Results: First, overexpression of VPS72 enhanced the initiation and progression of HCC in vitro and in vivo . Mechanistically, VPS72 interacted with the oncoproteins MYC and actin-like 6A (ACTL6A) and promoted the formation of the ACTL6A/MYC complex. Furthermore, ACTL6A regulated VPS72 protein stability by weakening the interaction between tripartite motif containing 21 (TRIM21) and VPS72. Thus, the interaction between VPS72 and ACTL6A enhanced the affinity of MYC for its target gene promoters and promoted their transcription, thereby contributing to HCC progression, which was inhibited by adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) against VPS72. Conclusions: This study reveals the molecular mechanism of ACTL6A/VPS72/MYC in HCC, providing a theoretical basis and therapeutic target for this malignancy.
Environmental eustress promotes liver regeneration through the sympathetic regulation of type 1 innate lymphoid cells to increase IL-22 in mice
Authors: Tingting Liu, Jin Li, Qian Li, Yiyi Liang, Jian Gao, Zihong Meng, Peiying Li, Ming Yao, Jinyang Gu, Hong Tu, Yu Gan
Journal: Hepatology (2023)

Background and Aims: The liver has the unique ability of regeneration, which is extremely important for restoring homeostasis after liver injury. Although clinical observations have revealed an association between psychological stress and the liver, whether stress has a causal influence on the liver regeneration remains markedly less defined. Approach and Results: Rearing rodents in an enriched environment (EE) can induce eustress or positive psychological stress. Herein, EE-induced eustress was found to significantly enhance the ability of liver regeneration after partial hepatectomy or carbon tetrachloride-induced liver injury based on the more rapid restoration of liver/body weight ratio and the significantly increased number of proliferating hepatocytes in EE mice. Mechanistically, the cytokine array revealed that IL-22 was markedly increased in the regenerating liver in response to EE. Blockade of IL-22 signaling abrogated the enhanced liver regeneration induced by EE. Group 1 innate lymphoid cells (ILCs), including type 1 ILCs (ILC1s), have been identified as the major sources of IL-22 in the regenerating liver. EE housing led to a rapid accumulation of hepatic ILC1s after partial hepatectomy and the EE-induced enhancement of liver regeneration and elevation of IL-22 was nearly eliminated in ILC1-deficient Tbx21 -/- mice. Chemical sympathectomy or blockade of β-adrenergic signaling also abolished the effect of EE on ILC1s and attenuated the enhanced liver regeneration of EE-housed mice. Conclusion: The study findings support the brain-liver axis and suggest that environment-induced eustress promotes liver regeneration through the sympathetic nerve/ILC1/IL-22 axis.
Risk Factors Associated With Peripartum Suicide Attempts in Japan
Authors: Tetsuya Akaishi, Kunio Tarasawa, Kiyohide Fushimi, Hirotaka Hamada, Masatoshi Saito, Natsuko Kobayashi, Saya Kikuchi, Hiroaki Tomita, Tadashi Ishii, Kenji Fujimori, Nobuo Yaegashi
Journal: JAMA Network Open (2023)

Importance Peripartum suicide attempt is a major psychiatric complication associated with pregnancy, but the risk factors remain largely uncertain. Objective To identify the demographic characteristics and predisposing risks for peripartum suicide attempts and postpartum depression. Design, Setting, and Participants This cohort study used retrospective data on pregnant women who delivered children between April 1, 2016, and March 31, 2021, at 712 hospitals in Japan. The nationwide Diagnosis Procedure Combination database was used. Exposures Psychiatric and nonpsychiatric medical history, age, alcohol and tobacco use, and obstetric complications and procedures. Main Outcomes and Measures Data on admissions for prepartum suicide attempt and delivery during the same hospital stay and readmissions for depression or suicide attempt within 1 year post partum were collected. Comparisons of prevalence of each study variable were performed, and multivariable logistic regression analyses were used to determine risk factors. Results From a total of 39 908 649 hospitalization episodes, 804 617 cumulative pregnant women (median [IQR] age at childbirth, 33 [29-36] years) who delivered at the enrolled hospitals were identified, including 1202 who were admitted for suicide attempt and delivery during the same hospital stay and 111 readmitted for suicide attempt within 1 year post partum. Risk factors associated with prepartum suicide attempts included younger age (adjusted odds ratio [aOR], 0.99; 95% CI, 0.98-1.00) and histories of personality disorder (aOR, 10.81; 95% CI, 5.70-20.49), depression (aOR, 3.97; 95% CI, 2.35-6.70), schizophrenia (aOR, 2.89; 95% CI, 1.52-5.50), and adjustment disorder (aOR, 2.66; 95% CI, 1.07-6.58). Risk factors associated with postpartum suicide attempts included younger age (aOR, 0.96; 95% CI, 0.93-1.00), heavy tobacco use (aOR, 23.09; 95% CI, 5.46-97.62), and histories of alcohol use disorder (aOR, 163.54; 95% CI, 28.30-944.95), personality disorder (aOR, 10.28; 95% CI, 3.29-32.10), anxiety disorders (aOR, 8.13; 95% CI, 2.88-22.98), depression (aOR, 7.27; 95% CI, 2.95-17.91), schizophrenia (aOR, 5.77; 95% CI, 2.17-15.38), bipolar disorder (aOR, 3.98; 95% CI, 1.36-11.67), and insomnia (aOR, 3.17; 95% CI, 1.30-7.78). On sensitivity analysis, risk factors associated with postpartum depression after excluding those with prenatal depression included histories of personality disorder, adjustment disorder, bipolar disorder, insomnia, and anxiety disorders. Conclusions and Relevance The findings of this cohort study suggest that histories of smoking and prenatal psychiatric disorders are potential risk factors for peripartum suicide attempts and may require additional treatment and prevention interventions.
EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection
Authors: David Capper, Guido Reifenberger, Pim J French, Leonille Schweizer, Michael Weller, Mehdi Touat, Simone P Niclou, Philipp Euskirchen, Christine Haberler, Monika E Hegi, Sebastian Brandner, Emilie Le Rhun, Roberta Rudà, Marc Sanson, Ghazaleh Tabatabai, Felix Sahm, Patrick Y Wen, Pieter Wesseling, Matthias Preusser, Martin J van den Bent
Journal: Neuro-Oncology (2023)

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.
Increasing gallstone disease prevalence and associations with gallbladder and biliary tract mortality in the US
Authors: Aynur Unalp-Arida, Constance E. Ruhl
Journal: Hepatology (2023)

Background and Aims: We examined gallbladder and biliary tract mortality predictors in the US National Health and Nutrition Examination Survey (NHANES), 1988-1994, with 31 years of linked mortality data, and gallstone disease prevalence trends and associations in NHANES 2017-March 2020 prepandemic data. Approach and Results: In NHANES 1988-1994, 18,794 participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to the National Death Index through 2019. In NHANES 2017-March 2020, gallstone disease history was ascertained from 9232 adults. During NHANES 1988-2019 follow-up (median, 23.3 y), 8580 deaths occurred from all causes and 72 deaths with gallbladder or biliary tract disease. In multivariable-adjusted analysis, older age, male sex, prediabetes or diabetes, and physical inactivity were associated with gallbladder and biliary tract mortality, and non-Hispanic Black and Mexican American race-ethnicity were inversely associated. Between 1988-1994 and 2017-March 2020, gallstone disease prevalence increased from 7.4% to 13.9% and gallbladder surgery from 6.0% to 11.6%. In 2017-March 2020 in multivariable-adjusted analysis, female sex, diabetes, liver disease, proton pump inhibitors, abdominal pain, increased age, BMI, and liver stiffness were associated with gallstone disease, and non-Hispanic Black and non-Hispanic Asian race and alcohol were inversely associated. Conclusions: In the US population, gallstone disease prevalence doubled over 3 decades, possibly because of the worsening of metabolic risk factors and growth of laparoscopic cholecystectomy. Gallbladder and biliary tract mortality and gallstone disease associations included factors such as prediabetes or diabetes, liver stiffness and proton pump inhibitors.
Evidence-Based Strategies to Reduce Suicide Mortality Among Patients With Cancer
Authors: Craig J. Bryan, Kristen M. Carpenter, Timothy M. Pawlik
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal